SARS‐CoV‐2 in patient with protein C deficiency: A case report

Key clinical message In SARS‐CoV‐2 pandemic different disorders in coagulation pathways in COVID‐19 patients were reported. We described a 44‐year‐old female with COVID‐19 and protein C deficiency history. She did not show any coagulation disorder during her disease course. Complete genome sequencing of SARS‐CoV‐2 was performed and some mutations identified and compared with Wuhan strain. Besides hospitalized patients, in COVID‐19 outpatients with low concentration of protein C, early prescription of an anticoagulant such as heparin could be helpful in prevention of venous thromboembolism or pulmonary embolism.


| INTRODUCTION
The novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), in the current pandemic is created many complications for patients all over the world.After reporting the first cases of COVID-19 in February 2020 in Iran we faced different forms of illness and complicated status in our country. 1SARS-CoV-2 can cause different manifestations like coagulation disorders and thrombotic complications in patients.The pathogenesis of the COVID-19-induced coagulopathy has not yet been fully elucidated.Thrombophilia is defined as the increased propensity of blood for development of the thrombose, that is proposed as a cause of hypercoagulability.It is possible that people with thrombophilia are susceptible to death due to COVID-19.Therefore, for prophylactic purpose and reduction of the risk of death low-weight heparin is suggested for administration. 2Protein C has anticoagulant role in coagulation pathway.The deficiency of protein C disturbs the balance between procoagulant and anticoagulant proteins, therefore, it may cause venous thromboembolism (VTE) and pulmonary embolism (PE). 3,4As coagulopathy is one of the COVID-19 complications, people with protein C deficiency may be susceptible to thrombotic complications. 5][8][9] Here we reported a COVID-19 case with protein C deficiency which with appropriate prophylaxis, she had not experienced thrombotic complications.
A 44-year-old female who had positive SARS-CoV-2 PCR test (Threshold Cycle Ct:30) on 4 November 2020 with symptoms of fatigue and lethargy.She had been in direct contact with a COVID-19 patient in 28 October 2020.Her SARS-CoV-2 PCR test was negative on 1 November 2020.After SARS-CoV-2 infection confirmation on 4 November, she was isolated with complete bed rest.The SARS-CoV-2 genomic sequencing data showed the circulation of GH clade from October to November 2020 in Iran. 10

| DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS, AND TREATMENT
The patient's primary laboratory tests were normal.On the third day of illness fever was 38°C and the patient's main complaint were fatigue, lethargy, insomnia, restlessness, and increased appetite with SPO 2 ; 92%-95%.Based on the history of protein C deficiency in patient, she received heparin 6000 unit every night since the first day of diagnosis.As a viral therapy since 5th November, Sovodak tablet (Sofosbuvir plus Daclatasvir) was ordered daily until 10 days.Vitamin C (500 mg), vitamin D (1000 mg), zinc plus and melatonin tablets daily and famotidine 40 mg BD were consumed.On the Day 9, patient suffered from shortness of breath.Computed tomography (CT) scan was performed which she had a unilateral lung involvement (Figure 1) and she was hospitalized on 14th November.On the day of hospitalization (Day 11), her PCR test was positive with Ct:25.In hospital she received five doses of remdesivir for 5 days.Dexamethasone injection and pantoprazole tablets BID were ordered.Electrocardiography (ECG) and echocardiography were performed due to acute chest pain which were normal.On Day 15, at the time of discharge from the hospital, PCR test was negative.During the acute phase of the diseases, liver enzymes were raised but after 1 month became normal.The patient's menstrual period was delayed for 18 days due to COVID-19.Laboratory findings include coagulation factors, biochemistry and complete blood count (CBC) were shown with comparison the results in different days of the illness in Table 1.It is worth mentioning that the D-Dimer level was reported negative on 5 days after infection.
For SARS-CoV-2 mutation analysis, full genome sequencing was performed on the patient's first sample with Illumina NextSeq at National Influenza Center, Tehran University of Medical Sciences.In SARS-CoV-2 genome sequencing, GH clade (Spike D614G and NS3 Q57H) was observed and some mutations in comparison with hCoV-19/Wuhan/WIV04/2019 strain were identified. 11(Table 2).

| DISCUSSION
In this report, we introduced a COVID-19 patient with protein C deficiency.During the SARS-CoV-2 pandemic, coagulation abnormalities in COVID-19 patients were reported, and proposed that COVID-19 patients with protein C deficiency faced with a risk factor for severe disease, 6,12 but there is no describing evidence about different symptoms and other complications in COVID-19 patients with protein C deficiency.Maqbool et al. reported a case with heterozygous protein C deficiency presented PE and myocardial infraction. 4A recent research reported that protein C and S deficiencies are current undiagnosed thrombophilia in the COVID-19 patients with severe outcome when compared with non-severe ones.It is possible that these undiagnosed disorders in the highrisk COVID-19 patients have a role in severe outcome and development of thrombosis. 13Elshafie et al. reported reduction in protein C and S activities in COVID-19 patients in comparison with healthy populations. 14  Several research stated that treatment with heparin (dalteparin, enoxaparin, etc.) is cardinal therapy in COVID-19-induced coagulopathy such as VTE and PE. 15,16Tang et al. recommended treatment with heparin following coagulopathy in severe COVID-19 patients and stated that it is related to better prognosis. 17They suggested beneficial properties for anticoagulants treatment primarily with low molecular weight heparin (LMWH) in COVID-19 patients which have the elevated D-Dimer and sepsis-induced coagulopathy (SIC).Noteworthy, the other studies have proposed non-coagulant effects for heparin especially anti-inflammatory roles in COVID-19 patients. 18he asymptomatic and undiagnosed thrombophilia in some situations such as hyper-estrogenic conditions (pregnancy and postpartum) might result in development of different disorders. 13A study had been stated that protein C deficiency plays role in fetal losses in pregnancies. 19In agreement with the mentioned phenomenon, our case due to protein C deficiency, had a history of intrauterine fetal death (IUFD) on her first pregnancy when protein C deficiency was undiagnosed and during the second pregnancy heparin was used with a healthy outcome.
In this report, the COVID-19 patient with protein C deficiency had lung involvement and liver enzymes abnormalities.Excluding the protein C deficiency, other coagulation parameters were normal, but for prophylaxis of possible complications, she started taking heparin since the first day of her disease.
In conclusion, following our observations in COVID-19 patients with protein C deficiency, besides hospitalized patients, it is better to start an anticoagulant also in outpatients under physician supervision and recommendation for prophylaxis of possible VTE or PE.
An investigation documented the relationship between low levels of protein C at the time of admission with severity and mortality of hospitalized COVID-19 individuals.12

F I G U R E 1
Computed tomography (CT) scan in COVID-19 patient with unilateral lung involvement.
Laboratory findings of the COVID-19 patient with protein C deficiency.